Targeting Lipid Oxidation for Prostate Cancer Imaging and Therapy

针对前列腺癌成像和治疗的脂质氧化

基本信息

批准号：
9123423
负责人：
Isabel Rubio Schlaepfer
金额：
$ 12.3万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-07 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123423
关键词：
Acetates Affect Apoptosis Apoptotic B-Lymphocytes Biological Markers Biopsy Burn injury Cancer Relapse Cell Respiration Cell Survival Cells Cessation of life Choline Detection Development Diagnostic Disease Drug resistance Enzymes FDA approved Failure Fatty acid glycerol esters Fatty-acid synthase Glucose Glycolysis Growth Hour Human Image Imaging Techniques Indolent Intervention LNCaP Lead Link Lipids Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolic Metabolic Pathway Metastatic Prostate Cancer Methods Mitochondria Molecular Mus Neoplasm Metastasis Outcome PSA screening Pathway interactions Phenotype Positron-Emission Tomography Protocols documentation Recurrence Role Signal Transduction Solid Source Staging Testing Therapeutic Therapeutic Intervention Tracer Warburg Effect Xenograft Model Xenograft procedure advanced disease aerobic glycolysis base bench to bedside cancer cell cancer imaging cancer survival cancer therapy combinatorial curative treatments design effective therapy etomoxir glucose metabolism glucose uptake improved inhibitor/antagonist innovation lipid metabolism mitochondrial metabolism novel oxidation oxidized lipid prostate cancer cell radiotracer ranolazine research study response screening stem tumor tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Title: Targeting Lipid Oxidation for Prostate Cancer Imaging and Therapy Rationale: Increased aerobic glycolysis is only observed in advanced metastatic prostate cancer (PCa), while de novo lipid synthesis can be observed in both primary and advanced PCa. These differences may be the reason why PCa tumors respond differently to Positron Emission Tomography (PET)-glucose imaging techniques: Advanced disease is imaged by PET-glucose but low grade prostate cancer tumors are not, suggesting different metabolic pathways between early and advanced/metastatic PCa. This proposal speculates that lipid oxidation supports glycolysis in PCa, and blocking lipid oxidation will lead to enhanced PET signal in PCa xenograft models, even in early stages. The clinically safe fat burning inhibitor etomoxir is able to block 14C-lipid oxidation in LNCaP cells, resulting in increased 14C-lipid trapped inside the cells and concomitant increases in glucose uptake. However, these metabolic changes result in 40% decreased viability of LNCaP cells by 48 hours suggesting that blocking fat oxidation perturbs their ability to use glucose (aerobic glycolysis) as a fuel source, resultin in apoptosis. Survival of non-cancer cells was not affected by etomoxir, suggesting an ability to switch to glucose oxidation for their fuel needs. This has great implications for how glucose and lipid metabolism interrelate, leading to novel metabolic approaches to image and treat PCa tumors. Hypothesis: Safely blocking lipid oxidation will result in accumulation of lipid metabolites, increased compensatory glucose uptake, but failure to maintain glycolysis, resulting in increased PET imaging signal and decreased PCa survival. Specific Aim 1: Study the proliferation, apoptosis, signaling and metabolites of tumorigenic and non- tumorigenic PCa cells exposed to lipid oxidation inhibitors. Results will identify the apoptotic mechanisms of etomoxir and ranolazine fat burning inhibitors and the metabolic biomarkers associated with the decreased PCa cell viability. These biomarkers can be used to design better PET tracers (glucose or lipid-based) that can be explored in Aim 2. Specific Aim 2: Utilize mouse PCa xenograft experiments to study growth, metabolite profile, oxidative metabolism, and PET imaging of tumors after systemic treatment with lipid oxidation inhibitors. Xenograft studies will provide verification of the new role of lipid oxidation in PCa tumor survival and will offer novel PET tracers to improve PCa imaging when combined with safe fat burning inhibitors. Knowing the amount of metabolites trapped inside the cells will help us design more effective PET tracers for PCa tumors and move our protocols from the bench to the bedside. Innovation: Lipid synthesis in prostate cancer has been observed for many years and inhibitors of FASN enzyme are currently being developed. However, new observations suggest that PCa is also a lipolytic cancer that depends on lipid mitochondrial metabolism for its survival, but little is known about the lipid synthesis- oxidation cycling that occurs in PCa and how it supports tumor growth. This lipid-cycling of PCa is a novel research study concept that will be examined by adapting existing metabolic methods. Disruption of the lipid cycle at the mitochondrial oxidation level will also be exploited for improved diagnostics, since specific unoxidized lipid metabolites that accumulate in the cells can be used to design new radiotracers for more effective imaging of PCa tumors. Since increased glucose uptake is also a response to lipid oxidation inhibition, PET-glucose will be enhanced in PCa cells unable to oxidize lipids. Thus, the proposed studies offer a new way to look at lipid metabolism in PCa cells, with strong potential for imaging and therapeutic interventions. Impact: Currently, only glycolytic PCa tumors are visible by PET-glucose and lipogenic tracers like 11C-choline or 11C-acetate are unable to detect small metastasis. In the long term, blocking fat oxidation with FDA approved fat inhibitors like ranolazine could lead to increased image signal of most PCa tumors, since glucose or lipid-based tracers would accumulate inside PCa cells, improving tumor detection, staging and response to therapy in a safe and effective manner. This proposal targets lipid oxidation pathways of PCa cells new Achilles' heel to be exploited for therapeutic (decreased PCa viability) and imaging (PET) outcomes. Furthermore, PCa relapse has no potential curative therapy, but it is associated with a lipid-dependent phenotype that will be exploited in the proposed studies to generate more effective therapy and imaging approaches to recurrent PCa tumors. Additionally, recent trials suggest that routine screening does not reduce PCa death and may lead to overtreatment, emphasizing the need for additional tests to supplement PSA screening and differentiate indolent from lethal disease.

描述（由申请人提供）：标题：针对前列腺癌成像和治疗的脂质氧化理由：有氧糖酵解增加仅在晚期转移性前列腺癌 (PCa) 中观察到，而在原发性和晚期 PCa 中都可以观察到从头脂质合成。这些差异可能是 PCa 肿瘤对正电子发射断层扫描 (PET)-葡萄糖成像技术的反应不同的原因：晚期疾病可通过 PET-葡萄糖成像，但低级别前列腺癌肿瘤则不然，这表明早期和晚期/转移性之间存在不同的代谢途径前列腺癌。该提议推测，脂质氧化支持 PCa 中的糖酵解，并且阻断脂质氧化将导致 PCa 异种移植模型中的 PET 信号增强，即使在早期阶段也是如此。临床上安全的脂肪燃烧抑制剂依托莫克西能够阻断 LNCaP 细胞中的 14C-脂质氧化，导致细胞内捕获的 14C-脂质增加，并伴随葡萄糖摄取增加。然而，这些代谢变化导致 LNCaP 细胞的活力在 48 小时内下降 40%，这表明阻断脂肪氧化会干扰它们使用葡萄糖（有氧糖酵解）作为燃料来源的能力，从而导致细胞凋亡。非癌细胞的存活不受依托莫克西的影响，这表明它们能够转向葡萄糖氧化来满足其燃料需求。这对于葡萄糖和脂质代谢如何相互关联具有重要意义，从而催生了对前列腺癌肿瘤进行成像和治疗的新代谢方法。假设：安全阻断脂质氧化将导致脂质代谢物积累，代偿性葡萄糖摄取增加，但无法维持糖酵解，导致 PET 成像信号增加和 PCa 存活率降低。具体目标 1：研究暴露于脂质氧化抑制剂的致瘤性和非致瘤性 PCa 细胞的增殖、凋亡、信号转导和代谢产物。结果将确定依托莫克西和雷诺嗪脂肪燃烧抑制剂的细胞凋亡机制以及与 PCa 细胞活力下降相关的代谢生物标志物。这些生物标志物可用于设计更好的 PET 示踪剂（基于葡萄糖或脂质），可在目标 2 中进行探索。具体目标 2：利用小鼠 PCa 异种移植实验来研究肿瘤的生长、代谢物谱、氧化代谢和 PET 成像。使用脂质氧化抑制剂进行全身治疗。异种移植研究将验证脂质氧化在 PCa 肿瘤存活中的新作用，并将提供新型 PET 示踪剂，与安全的脂肪燃烧抑制剂结合使用时可改善 PCa 成像。了解细胞内代谢物的数量将有助于我们设计更有效的 PCa 肿瘤 PET 示踪剂，并将我们的方案从实验室转移到临床。创新：前列腺癌中的脂质合成已被观察多年，目前正在开发 FASN 酶的抑制剂。然而，新的观察结果表明前列腺癌也是一种脂肪分解癌症，其生存依赖于脂质线粒体代谢，但人们对前列腺癌中发生的脂质合成-氧化循环及其如何支持肿瘤生长知之甚少。 PCa 的脂质循环是一个新颖的研究概念，将通过采用现有的代谢方法进行检验。线粒体氧化水平上脂质循环的破坏也将用于改进诊断，因为细胞中积累的特定未氧化脂质代谢物可用于设计新的放射性示踪剂，以便更有效地对 PCa 肿瘤进行成像。由于葡萄糖摄取增加也是对脂质氧化抑制的反应，因此在无法氧化脂质的 PCa 细胞中 PET-葡萄糖将会增强。因此，拟议的研究提供了一种观察 PCa 细胞脂质代谢的新方法，具有强大的成像和治疗干预潜力。影响：目前，PET-葡萄糖只能观察到糖酵解性 PCa 肿瘤，而 11C-胆碱或 11C-乙酸盐等脂肪生成示踪剂无法检测到小转移。从长远来看，使用 FDA 批准的脂肪抑制剂（如雷诺嗪）阻断脂肪氧化可能会导致大多数 PCa 肿瘤的图像信号增加，因为葡萄糖或脂质示踪剂会在 PCa 细胞内积聚，从而改善肿瘤检测、分期和对治疗的反应。安全有效的方式。该提案针对 PCa 细胞的脂质氧化途径这一新的致命弱点，用于治疗（PCa 活力降低）和成像 (PET) 结果。此外，PCa 复发没有潜在的治愈疗法，但它与脂质依赖性表型相关，将在拟议的研究中利用这一表型来产生针对复发性 PCa 肿瘤的更有效的治疗和成像方法。此外，最近的试验表明，常规筛查并不能减少 PCa 死亡，并可能导致过度治疗，强调需要进行额外的测试来补充 PSA 筛查并区分惰性疾病和致命疾病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RTN4 Knockdown Dysregulates the AKT Pathway, Destabilizes the Cytoskeleton, and Enhances Paclitaxel-Induced Cytotoxicity in Cancers.

RTN4 敲低会导致 AKT 通路失调、细胞骨架不稳定并增强癌症中紫杉醇诱导的细胞毒性。

DOI：
10.1016/j.ymthe.2018.05.026
发表时间：
2018-08-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
Gopal P. Pathak;Rashmi Shah;Barry E. Kennedy;J. P. Murphy;D. Clements;Prathyusha Konda;Michael A Giacomantonio;Zhaolin Xu;I. Schlaepfer;S. Gujar
通讯作者：
S. Gujar

Raman and coherent anti-Stokes Raman scattering microscopy studies of changes in lipid content and composition in hormone-treated breast and prostate cancer cells.

拉曼和相干反斯托克斯拉曼散射显微镜研究激素处理的乳腺癌和前列腺癌细胞中脂质含量和成分的变化。

DOI：
发表时间：
2014
期刊：
影响因子：
3.5
作者：
Potcoava, Mariana C;Futia, Gregory L;Aughenbaugh, Jessica;Schlaepfer, Isabel R;Gibson, Emily A
通讯作者：
Gibson, Emily A

Aberrant Lipid Metabolism Promotes Prostate Cancer: Role in Cell Survival under Hypoxia and Extracellular Vesicles Biogenesis.

异常的脂质代谢促进前列腺癌：缺氧和细胞外囊泡生物发生下细胞存活的作用。

DOI：
发表时间：
2016-07-02
期刊：
影响因子：
5.6
作者：
Deep, Gagan;Schlaepfer, Isabel R
通讯作者：
Schlaepfer, Isabel R

Raman Microscopy Techniques to Study Lipid Droplet Composition in Cancer Cells.

研究癌细胞中脂滴成分的拉曼显微镜技术。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Potcoava, Mariana C;Futia, Gregory L;Gibson, Emily A;Schlaepfer, Isabel R
通讯作者：
Schlaepfer, Isabel R

Lipid profiling using Raman and a modified support vector machine algorithm.

使用拉曼和改进的支持向量机算法进行脂质分析。

DOI：
10.1002/jrs.6238
发表时间：
2021-11
期刊：
Journal of Raman spectroscopy : JRS
影响因子：
0
作者：
Potcoava, Mariana C.;Futia, Gregory L.;Gibson, Emily A.;Schlaepfer, Isabel R.
通讯作者：
Schlaepfer, Isabel R.